SummaryThis report compares the pharmacokinetics and the bioavailabilities of the antifactor Xa and of the antifactor II a activities generated by intravenous (IV) and subcutaneous (SC) injections of increasing doses of unfractionated heparin (UH) and of a low molecular weight heparin (CY 216). Rabbits were injected with 500, 1,000, 2,500 and 5,000 antifactor Xa u/kg of both heparins and their biological activities were followed at various time intervals. After IV injection the clearance of the antifactor Xa activities was independent of the dose and the clearance of UH was significantly higher than that of CY 216; after SC injection the bioavailability estimated from the antifactor Xa effect was consistently over 100% for CY 216 while that of UH increased from 27% at the lowest dose to 93% at the highest dose. The pharmacokinetic parameters estimated by the antifactor IIa activity of UH were superimposable to those calculated with the antifactor Xa activity. For CY 216 no direct comparison between the two activities was made since the dose injected expressed in antifactor IIa units was 3.4 times lower. UH and CY 216 were therefore injected intravenously to other animals at equivalent and increasing doses expressed in antifactor IIa units (50-5,000 u/kg). The pharmacokinetic parameters calculated from the curves of the antifactor IIa activities were basically identical except at the two lower doses (50 and 100 u/kg) for which UH was cleared faster than CY 216. These results indicate that the antifactor IIa activity generated by an injection of CY 216 disappears faster than the corresponding antifactor Xa activity and therefore that the antifactor Xa/antifactor IIa activity ratio of CY 216 progressively increases after SC or IV injection.
Standard unfractionated heparin is a polydisperse compound with a molecular weight ranging from 2.5 to 30 kd. During the last 10 years, considerable interest has been devoted to low molecular weight fragments or fractions of heparin (LMWH), which have some biologic properties that differ from those of standard unfractionated heparin (in the rest of the discussion, heparin will be used instead of standard unfractionated heparin). This short review summarizes current knowledge on the pharmacokinetics and pharmacodynamics of heparin and of LMWH. We will first discuss some difficulties inherent to the pharmacokinetic study of heparin, which may explain the many variations reported in the literature. The kinetics of the disappearance of the anticoagulant effect of unfractionated heparin reflect the behavior of approximately one-third of the molecules that bind antithrombin III with high affinity. In contrast, disappearance curves that are based on the radioactivity of the labeled heparin molecules recovered in blood represent all of the heparin molecules in the blood compartment regardless of their affinity to antithrombin III. We will describe a pharmacokinetic model of heparin in the rabbit that helps to explain why the half-life of heparin is dosedependent and why the shape of the curve that describes the disappearance of the anticoagulant activity after a bolus injection of large doses of heparin is concave-convex. This model also explains the better bioavailability of LMWH when compared with heparin. DIFFICULTIES IN ASSESSING THE PHARMACOKINETICS OF HEPARINThe disappearance of heparin may be investigated either by biologic assays (pharmacodynamics) or by estimating the rates of disappearance of radiolabeled heparin (pharmacokinetics). These two approaches yield different results for these specific parameters. The anticoagulant or biologic effect of heparin is estimated routinely by a variety of assays, including the activated partial thromboplastin time (APTT), or the antithrombin and the anti-Factor Xa effects. Three-to fourfold differences in the half-life of heparin have been reported when the half-life of heparin is calculated from the ex vivo clotting time data rather than its anti-Factor Xa effects. 1 In another study the prolongation of the APTT was converted into heparin units using appropriate calibration curves. 2 Using such an approach, the ex vivo concentrations of heparin were found to be lower than those measured by the anti-Factor Xa assays. 2 More recently, other investigators have compared the pharmacokinetic profiles of heparin and LMWH using either a competitive binding assay (which measures the heparin concentration expressed in µg/m) or an anti-Factor Xa assay. 3,4 The duration of the antiFactor Xa effect was longer than the concentration
Our purpose was to determine the relative contribution of the antifactor Xa and antithrombin activities of heparin to its antithrombotic potency. The antithrombotic activities of unfractionated heparin (UH), two low molecular weight heparins (LMWH, CY 216 and CY 222) with increasing anti-factor Xa/antithrombin ratio and a synthetic pentasaccharide (PS) with high affinity to antithrombin III and no antithrombin activity were evaluated. In the Wessler-thromboplastin model, the most potent antithrombotic agent, on a weight basis, was UH followed by CY 216, CY 222 and the PS which was 40 times less potent than UH. On an antithrombin unit basis, the antithrombotic potencies of UH, CY 216 and of CY 222 were equivalent. Thus, in this model, the antithrombotic effect results from the catalytic action of UH or LMWH on thrombin inhibition. In the Wessler-serum model, on a weight basis, the antithrombotic effectiveness of UH was unchanged, those of CY 216 and CY 222 were doubled, and that of the PS was increased 10 times. On an anti-factor Xa unit basis, CY 216 was as effective as UH, and PS as effective as CY 222. On an antithrombin unit basis, CY 216 and CY 222 were equivalent and more potent than UH. Thus, in this model, the antifactor Xa activity of heparin becomes important for its antithrombotic property. After a single subcutaneous injection of 1000 antifactor Xa U/kg, the antithrombotic effects of UH were maintained for more than 14 h in the two models. After injection of the same dose of CY 216 significant antithrombotic effects were observed only for 9 h, in the Wessler-thromboplastin model but for 18 h in the Wessler-serum model. At that time, no detectable antithrombin activity was measurable in the plasma while 0.11 units of antifactor Xa activity/ml was detected. Thus, the relative contribution of the anti-factor Xa and antithrombin activities to the antithrombotic effect of a LMWH differs according to the nature of the thrombogenic stimulus.
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